Elevated transcript levels from the MDM2 P1 promoter and low p53 transcript levels are associated with poor prognosis in human pancreatic ductal adenocarcinoma.

Abstract:

UNLABELLED:OBJECTDIVES: Mouse double minute 2 is a key negative regulator of the p53 protein, a central node in the mediation of tumor suppression. The MDM2 gene contains 2 differently regulated promoters, MDM2-P1 and MDM2-P2, which differ strongly in their biological and clinical importance. METHODS:We assess the clinical significance of the expression of messenger RNA (mRNA) transcripts originating from both MDM2 promoters, measured with quantitative reverse transcription polymerase chain reaction in microdissected tissues from 57 patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, we determine the clinical relevance of p53 mRNA transcript expression and incorporate the somatic p53 mutational status into our analyses. RESULTS:Interestingly, elevated transcript levels from the P1 promoter, but not the P2 promoter, associate significantly with up to 6.3-fold increased relative risk for tumor-related death (Cox multivariate analysis: P = 0.013). Furthermore, transcripts originating from both MDM2 promoters are found to correlate significantly with p53 mRNA levels (up to r = 0.315; P = 0.017). In addition, low p53 mRNA expression associates with worse PDAC prognosis (relative risk = 2.28; P = 0.021). CONCLUSIONS:This study presents the first differentiated analysis of the MDM2-P1, MDM2-P2, and p53 transcript expression in human PDAC and demonstrates the significant clinical implications of those transcripts. Furthermore, it suggests an additional facet in the regulation of MDM2 via its P1 promoter in this malignancy.

journal_name

Pancreas

journal_title

Pancreas

authors

Grochola LF,Taubert H,Greither T,Bhanot U,Udelnow A,Würl P

doi

10.1097/mpa.0b013e3181f95104

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

265-70

issue

2

eissn

0885-3177

issn

1536-4828

journal_volume

40

pub_type

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